Nested Selves: Self-Organization and Shared Markov Blankets in Prenatal Development in Humans.

The immune system is a central component of organismic function in humans. This paper addresses self-organization of biological systems in relation to-and nested within-other biological systems in pregnancy. Pregnancy constitutes a fundamental state for human embodiment and a key step in the evolution and conservation of our species. While not all humans can be pregnant, our initial state of emerging and growing within another person's body is universal. Hence, the pregnant state does not concern some individuals but all individuals. Indeed, the hierarchical relationship in pregnancy reflects an even earlier autopoietic process in the embryo by which the number of individuals in a single blastoderm is dynamically determined by cell- interactions. The relationship and the interactions between the two self-organizing systems during pregnancy may play a pivotal role in understanding the nature of biological self-organization per se in humans. Specifically, we consider the role of the immune system in biological self-organization in addition to neural/brain systems that furnish us with a sense of self. We examine the complex case of pregnancy, whereby two immune systems need to negotiate the exchange of resources and information in order to maintain viable self-regulation of nested systems. We conclude with a proposal for the mechanisms-that scaffold the complex relationship between two self-organising systems in pregnancy-through the lens of the Active Inference, with a focus on shared Markov blankets.

Global disparities in availability of epinephrine auto-injectors.

Background: Anaphylaxis is the most severe clinical presentation of acute systemic allergic reactions and can cause death. Given the prevalence of anaphylaxis within healthcare systems, it is a high priority public health issue. However, management of anaphylaxis - both acute and preventative - varies by region. Methods: The World Allergy Organization (WAO) Anaphylaxis Committee and the WAO Junior Members Steering Group undertook a global online survey to evaluate local practice in the diagnosis and management of anaphylaxis across regions. Results: Responses were received from WAO members in 66 countries. While intramuscular epinephrine (adrenaline) is first-line treatment for anaphylaxis, some countries continue to recommend alternative routes in contrast to guidelines. Epinephrine auto-injector (EAI) devices, prescribed to individuals at ongoing risk of anaphylaxis in the community setting, are only available in 60% of countries surveyed, mainly in high-income countries. Many countries in South America, Africa/Middle-East and Asian-Pacific regions do not have EAI available, or depend on individual importation. In countries where EAIs are commercially available, national policies regarding the availability of EAIs in public settings are limited to few countries (16%). There is no consensus regarding the time patients should be observed following emergency treatment of anaphylaxis. Conclusion: This survey provides a global snapshot view of the current management of anaphylaxis, and highlights key unmet needs including the global availability of epinephrine for self-injection as a key component of anaphylaxis management.

Shock Index in the early assessment of febrile children at the emergency department: a prospective multicentre study.

OBJECTIVE: (1) To derive reference values for the Shock Index (heart rate/systolic blood pressure) based on a large emergency department (ED) population of febrile children and (2) to determine the diagnostic value of the Shock Index for serious illness in febrile children. DESIGN/SETTING: Observational study in 11 European EDs (2017-2018). PATIENTS: Febrile children with measured blood pressure. MAIN OUTCOME MEASURES: Serious bacterial infection (SBI), invasive bacterial infection (IBI), immediate life-saving interventions (ILSIs) and intensive care unit (ICU) admission. The association between high Shock Index (>95th centile) and each outcome was determined by logistic regression adjusted for age, sex, referral, comorbidity and temperature. Additionally, we calculated sensitivity, specificity and negative/positive likelihood ratios (LRs). RESULTS: Of 5622 children, 461 (8.2%) had SBI, 46 (0.8%) had IBI, 203 (3.6%) were treated with ILSI and 69 (1.2%) were ICU admitted. High Shock Index was associated with SBI (adjusted OR (aOR) 1.6 (95% CI 1.3 to 1.9)), ILSI (aOR 2.5 (95% CI 2.0 to 2.9)), ICU admission (aOR 2.2 (95% CI 1.4 to 2.9)) but not with IBI (aOR: 1.5 (95% CI 0.6 to 2.4)). For the different outcomes, sensitivity for high Shock Index ranged from 0.10 to 0.15, specificity ranged from 0.95 to 0.95, negative LRs ranged from 0.90 to 0.95 and positive LRs ranged from 1.8 to 2.8. CONCLUSIONS: High Shock Index is associated with serious illness in febrile children. However, its rule-out value is insufficient which suggests that the Shock Index is not valuable as a screening tool for all febrile children at the ED.

hnRNP A/B Proteins: An Encyclopedic Assessment of Their Roles in Homeostasis and Disease.

The hnRNP A/B family of proteins is canonically central to cellular RNA metabolism, but due to their highly conserved nature, the functional differences between hnRNP A1, A2/B1, A0, and A3 are often overlooked. In this review, we explore and identify the shared and disparate homeostatic and disease-related functions of the hnRNP A/B family proteins, highlighting areas where the proteins have not been clearly differentiated. Herein, we provide a comprehensive assembly of the literature on these proteins. We find that there are critical gaps in our grasp of A/B proteins' alternative splice isoforms, structures, regulation, and tissue and cell-type-specific functions, and propose that future mechanistic research integrating multiple A/B proteins will significantly improve our understanding of how this essential protein family contributes to cell homeostasis and disease.

The Risk of Allergic Reaction to SARS-CoV-2 Vaccines and Recommended Evaluation and Management: A Systematic Review, Meta-Analysis, GRADE Assessment, and International Consensus Approach.

Concerns for anaphylaxis may hamper severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunization efforts. We convened a multidisciplinary group of international experts in anaphylaxis composed of allergy, infectious disease, emergency medicine, and front-line clinicians to systematically develop recommendations regarding SARS-CoV-2 vaccine immediate allergic reactions. Medline, EMBASE, Web of Science, the World Health Organizstion (WHO) global coronavirus database, and the gray literature (inception, March 19, 2021) were systematically searched. Paired reviewers independently selected studies addressing anaphylaxis after SARS-CoV-2 vaccination, polyethylene glycol (PEG) and polysorbate allergy, and accuracy of allergy testing for SARS-CoV-2 vaccine allergy. Random effects models synthesized the data to inform recommendations based on the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach, agreed upon using a modified Delphi panel. The incidence of SARS-CoV-2 vaccine anaphylaxis is 7.91 cases per million (n = 41,000,000 vaccinations; 95% confidence interval [95% CI] 4.02-15.59; 26 studies, moderate certainty), the incidence of 0.15 cases per million patient-years (95% CI 0.11-0.2), and the sensitivity for PEG skin testing is poor, although specificity is high (15 studies, very low certainty). We recommend vaccination over either no vaccination or performing SARS-CoV-2 vaccine/excipient screening allergy testing for individuals without history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient, and a shared decision-making paradigm in consultation with an allergy specialist for individuals with a history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient. We recommend further research to clarify SARS-CoV-2 vaccine/vaccine excipient testing utility in individuals potentially allergic to SARS-CoV2 vaccines or their excipients.

Assessment of the Pathogenicity of Rickettsia amblyommatis, Rickettsia bellii, and Rickettsia montanensis in a Guinea Pig Model.

Members of the genus Rickettsia range from nonpathogenic endosymbionts to virulent pathogens such as Rickettsia rickettsii, the causative agent of Rocky Mountain spotted fever. Many rickettsiae are considered nonpathogenic because they have been isolated from ticks but not vertebrate hosts. We assessed the ability of three presumed endosymbionts: Rickettsia amblyommatis, Rickettsia bellii, and Rickettsia montanensis, to infect a guinea pig animal model. These species were chosen because of their high prevalence in respective tick vectors or published reports suggestive of human or animal pathogenicity. Following intraperitoneal (IP) inoculation of cell culture suspensions of R. rickettsii, R. amblyommatis, R. bellii, or R. montanensis into guinea pigs, animals were monitored for signs of clinical illness for 13 days. Ear biopsies and blood samples were taken at 2- to 3-day intervals for detection of rickettsial DNA by PCR. Animals were necropsied and internal organ samples were also tested using PCR assays. Among the six guinea pigs inoculated with R. amblyommatis, fever, orchitis, and dermatitis were observed in one, one, and three animals respectively. In R. bellii-exposed animals, we noted fever in one of six animals, orchitis in one, and dermatitis in two. No PCR-positive tissues were present in either the R. amblyommatis- or R. bellii-exposed groups. In the R. montanensis-exposed group, two of six animals became febrile, two had orchitis, and three developed dermatitis in ears or footpads. R. montanensis DNA was detected in ear skin biopsies collected on multiple days from three animals. Also, a liver specimen from one animal and spleen specimens of two animals were PCR positive. The course and severity of disease in the three experimental groups were significantly milder than that of R. rickettsii. This study suggests that the three rickettsiae considered nonpathogenic can cause either subclinical or mild infections in guinea pigs when introduced via IP inoculation.

Respiratory Tract Infection Management and Antibiotic Prescription in Children: A Unique Study Comparing Three Levels of Healthcare in The Netherlands.

BACKGROUND: Respiratory tract infections (RTIs) are common in children with febrile illness visiting the general practitioner (GP) or emergency department. We studied the management of children with fever and RTI at 3 different levels of healthcare in The Netherlands, focusing on antibiotic prescription. METHODS: This prospective observational study is part of the Management and Outcome of Febrile children in Europe study. Data were used from face-to-face patient contacts of children with febrile illness in three healthcare settings in Nijmegen, The Netherlands during 2017. These settings were primary (GP), secondary (general hospital) and tertiary care (university hospital). RESULTS: Of 892 cases with RTI without complex comorbidities, overall antibiotic prescription rates were 29% with no differences between the 3 levels of healthcare, leading to an absolute number of 5031 prescriptions per 100,000 children per year in primary care compared with 146 in secondary and tertiary care combined. The prescription rate in otitis media was similar in all levels: 60%. In cases with lower RTI who received nebulizations prescription rates varied between 19% and 55%. CONCLUSIONS: Antibiotic prescription rates for RTIs in children were comparable between the 3 levels of healthcare, thus leading to a majority of antibiotics being prescribed in primary care. Relatively high prescription rates for all foci of RTIs were found, which was not in agreement with the national guidelines. Antibiotic stewardship needs improvement at all 3 levels of healthcare. Guidelines to prescribe small spectrum antibiotics for RTIs need to be better implemented in hospital care settings.

An Ecological Momentary Assessment Study Investigating the Function of Hoarding.

This study examined the function of hoarding behaviors and the relations between hoarding and a series of cognitive and affective processes in the moment using ecological momentary assessment. A matched-groups design was used to compare college students with higher hoarding symptoms (n = 31) and matched controls (n = 29). The two groups did not differ in what function they reported acquiring served, and positive automatic reinforcement was the most commonly reported function in both groups. Engaging in hoarding-relevant behaviors did not predict change in positive or negative affect when controlling for previous affect. Emotional reactivity and experiential avoidance in the moment were both elevated in the higher hoarding group compared to controls, while momentary mindfulness and negative affect differentiation were lower. Overall, these findings support the importance of emotion regulation processes in hoarding. They also suggest individuals may not be successfully regulating affect in the moment with hoarding behaviors, despite efforts to do so. It may be useful to evaluate processes such as striving for positive affect in hoarding disorder in the future.

Assessment of Enrichment of Human Mesenchymal Stem Cells Based on Plasma and Mitochondrial Membrane Potentials.

Background: Human mesenchymal stem cells (hMSCs) are utilized preclinically and clinically as a candidate cell therapy for a wide range of inflammatory and degenerative diseases. Despite promising results in early clinical trials, consistent outcomes with hMSC-based therapies have proven elusive in many of these applications. In this work, we attempt to address this limitation through the design of a stem cell therapy to enrich hMSCs for desired electrical and ionic properties with enhanced stemness and immunomodulatory/regenerative capacity. Materials and Methods: In this study, we sought to develop initial protocols to achieve electrically enriched hMSCs (EE-hMSCs) with distinct electrical states and assess the potential relationship with respect to hMSC state and function. We sorted hMSCs based on fluorescence intensity of tetramethylrhodamine ethyl ester (TMRE) and investigated phenotypic differences between the sorted populations. Results: Subpopulations of EE-hMSCs exhibit differential expression of genes associated with senescence, stemness, immunomodulation, and autophagy. EE-hMSCs with low levels of TMRE, indicative of depolarized membrane potential, have reduced mRNA expression of senescence-associated markers, and increased mRNA expression of autophagy and immunomodulatory markers relative to EE-hMSCs with high levels of TMRE (hyperpolarized). Conclusions : This work suggests that the utilization of EE-hMSCs may provide a novel strategy for cell therapies, enabling live cell enrichment for distinct phenotypes that can be exploited for different therapeutic outcomes.

A simple crowdsourced delay-based traffic signal control.

Current transportation management systems rely on physical sensors that use traffic volume and queue-lengths. These physical sensors incur significant capital and maintenance costs. The ubiquity of mobile devices has made possible access to accurate and cheap traffic delay data. However, current traffic signal control algorithms do not accommodate the use of such data. In this paper, we propose a novel parsimonious model to utilize real-time crowdsourced delay data for traffic signal management. We demonstrate the versatility and effectiveness of the data and the proposed model on seven different intersections across three cities and two countries. This signal system provides an opportunity to leapfrog from physical sensors to low-cost, reliable crowdsourced data.

Neural control of body-plan axis in regenerating planaria.

Control of axial polarity during regeneration is a crucial open question. We developed a quantitative model of regenerating planaria, which elucidates self-assembly mechanisms of morphogen gradients required for robust body-plan control. The computational model has been developed to predict the fraction of heteromorphoses expected in a population of regenerating planaria fragments subjected to different treatments, and for fragments originating from different regions along the anterior-posterior and medio-lateral axis. This allows for a direct comparison between computational and experimental regeneration outcomes. Vector transport of morphogens was identified as a fundamental requirement to account for virtually scale-free self-assembly of the morphogen gradients observed in planarian homeostasis and regeneration. The model correctly describes altered body-plans following many known experimental manipulations, and accurately predicts outcomes of novel cutting scenarios, which we tested. We show that the vector transport field coincides with the alignment of nerve axons distributed throughout the planarian tissue, and demonstrate that the head-tail axis is controlled by the net polarity of neurons in a regenerating fragment. This model provides a comprehensive framework for mechanistically understanding fundamental aspects of body-plan regulation, and sheds new light on the role of the nervous system in directing growth and form.

Life-threatening infections in children in Europe (the EUCLIDS Project): a prospective cohort study.

BACKGROUND: Sepsis and severe focal infections represent a substantial disease burden in children admitted to hospital. We aimed to understand the burden of disease and outcomes in children with life-threatening bacterial infections in Europe. METHODS: The European Union Childhood Life-threatening Infectious Disease Study (EUCLIDS) was a prospective, multicentre, cohort study done in six countries in Europe. Patients aged 1 month to 18 years with sepsis (or suspected sepsis) or severe focal infections, admitted to 98 participating hospitals in the UK, Austria, Germany, Lithuania, Spain, and the Netherlands were prospectively recruited between July 1, 2012, and Dec 31, 2015. To assess disease burden and outcomes, we collected demographic and clinical data using a secured web-based platform and obtained microbiological data using locally available clinical diagnostic procedures. FINDINGS: 2844 patients were recruited and included in the analysis. 1512 (53·2%) of 2841 patients were male and median age was 39·1 months (IQR 12·4-93·9). 1229 (43·2%) patients had sepsis and 1615 (56·8%) had severe focal infections. Patients diagnosed with sepsis had a median age of 27·6 months (IQR 9·0-80·2), whereas those diagnosed with severe focal infections had a median age of 46·5 months (15·8-100·4; p<0·0001). Of 2844 patients in the entire cohort, the main clinical syndromes were pneumonia (511 [18·0%] patients), CNS infection (469 [16·5%]), and skin and soft tissue infection (247 [8·7%]). The causal microorganism was identified in 1359 (47·8%) children, with the most prevalent ones being Neisseria meningitidis (in 259 [9·1%] patients), followed by Staphylococcus aureus (in 222 [7·8%]), Streptococcus pneumoniae (in 219 [7·7%]), and group A streptococcus (in 162 [5·7%]). 1070 (37·6%) patients required admission to a paediatric intensive care unit. Of 2469 patients with outcome data, 57 (2·2%) deaths occurred: seven were in patients with severe focal infections and 50 in those with sepsis. INTERPRETATION: Mortality in children admitted to hospital for sepsis or severe focal infections is low in Europe. The disease burden is mainly in children younger than 5 years and is largely due to vaccine-preventable meningococcal and pneumococcal infections. Despite the availability and application of clinical procedures for microbiological diagnosis, the causative organism remained unidentified in approximately 50% of patients. FUNDING: European Union's Seventh Framework programme.

Mortality and morbidity in community-acquired sepsis in European pediatric intensive care units: a prospective cohort study from the European Childhood Life-threatening Infectious Disease Study (EUCLIDS).

BACKGROUND: Sepsis is one of the main reasons for non-elective admission to pediatric intensive care units (PICUs), but little is known about determinants influencing outcome. We characterized children admitted with community-acquired sepsis to European PICUs and studied risk factors for mortality and disability. METHODS: Data were collected within the collaborative Seventh Framework Programme (FP7)-funded EUCLIDS study, which is a prospective multicenter cohort study aiming to evaluate genetic determinants of susceptibility and/or severity in sepsis. This report includes 795 children admitted with community-acquired sepsis to 52 PICUs from seven European countries between July 2012 and January 2016. The primary outcome measure was in-hospital death. Secondary outcome measures were PICU-free days censured at day 28, hospital length of stay, and disability. Independent predictors were identified by multivariate regression analysis. RESULTS: Patients most commonly presented clinically with sepsis without a source (n = 278, 35%), meningitis/encephalitis (n = 182, 23%), or pneumonia (n = 149, 19%). Of 428 (54%) patients with confirmed bacterial infection, Neisseria meningitidis (n = 131, 31%) and Streptococcus pneumoniae (n = 78, 18%) were the main pathogens. Mortality was 6% (51/795), increasing to 10% in the presence of septic shock (45/466). Of the survivors, 31% were discharged with disability, including 24% of previously healthy children who survived with disability. Mortality and disability were independently associated with S. pneumoniae infections (mortality OR 4.1, 95% CI 1.1-16.0, P = 0.04; disability OR 5.4, 95% CI 1.8-15.8, P < 0.01) and illness severity as measured by Pediatric Index of Mortality (PIM2) score (mortality OR 2.8, 95% CI 1.3-6.1, P < 0.01; disability OR 3.4, 95% CI 1.8-6.4, P < 0.001). CONCLUSIONS: Despite widespread immunization campaigns, invasive bacterial disease remains responsible for substantial morbidity and mortality in critically ill children in high-income countries. Almost one third of sepsis survivors admitted to the PICU were discharged with some disability. More research is required to delineate the long-term outcome of pediatric sepsis and to identify interventional targets. Our findings emphasize the importance of improved early sepsis-recognition programs to address the high burden of disease.

Prospective assessment of positioning-related pain in robotic urologic surgery.

This was a prospective study to assess positioning-related pain in 20 awake volunteers in the dorsal lithotomy (DL) and lateral decubitus (LD) positions. Each volunteer was put through the series of discrete, sequential steps used to achieve a final position; each step had two options. The Wong-Baker scale (WB) was used to rate pain for each option and the preferred option and ad lib comments were recorded. We found that awake volunteers could clearly and immediately distinguish differences in pain levels between position options. For the DL position, volunteers favored having the arms slightly flexed and pronated as opposed to being straight and supinated reflected by statistically less painful WB scores and option preference. Volunteers preferred having the neck flexed as opposed to being flat. For the LD position, volunteers reported statistically lower pain scores and preference for a foam roll for axilla support as opposed to a rolled blanket, the table flexed without the kidney rest as opposed to a raised kidney rest, and the over arm board as oppose to stacked blankets for contralateral arm support. Ad lib comments from the volunteers supported the above findings. To our knowledge, ours is the first study to demonstrate objective preferences for variations in surgical positioning using awake volunteers. This exercise with awake volunteers resulted in immediate changes in positioning for real robotic surgery patients in our practice.

Data on survival of recent births as a source of child mortality estimates in the developing world: An assessment of census data.

In many less developed countries, household surveys collect full and summary birth histories to provide estimates of child mortality. However, full birth histories are expensive to collect and cannot provide precise estimates for small areas, and summary birth histories only provide past child mortality trends. A simple method that provides estimates for the most recent past uses questions about the survival of recent births in censuses or large household surveys. This study examines such data collected by 45 censuses and shows that on average they tend to underestimate under-5 mortality in comparison with alternative estimates, albeit with wide variations. In addition, the high non-sampling uncertainty in this approach precludes its use in providing robust estimates of child mortality at the country level. Given these findings, we suggest that questions about the survival of recent births to collect data on child mortality not be included in census questionnaires.

Assessment of Domestic Goats as Models for Experimental and Natural Infection with the North American Isolate of Rickettsia slovaca.

Rickettsia slovaca is a tick-borne human pathogen that is associated with scalp eschars and neck lymphadenopathy known as tick-borne lymphadenopathy (TIBOLA) or Dermacentor-borne necrosis erythema and lymphadenopathy (DEBONEL). Originally, R. slovaca was described in Eastern Europe, but since recognition of its pathogenicity, human cases have been reported throughout Europe. European vertebrate reservoirs of R. slovaca remain unknown, but feral swine and domestic goats have been found infected or seropositive for this pathogen. Recently, a rickettsial pathogen identical to R. slovaca was identified in, and isolated from, the American dog tick, Dermacentor variabilis. In previous experimental studies, this organism was found infectious to guinea pigs and transovarially transmissible in ticks. In this study, domestic goats (Capra hircus) were experimentally inoculated with the North American isolate of this R. slovaca-like agent to assess their reservoir competence-the ability to acquire the pathogens and maintain transmission between infected and uninfected ticks. Goats were susceptible to infection as demonstrated by detection of the pathogen in skin biopsies and multiple internal tissues, but the only clinical sign of illness was transient fever noted in three out of four goats, and reactive lymphoid hyperplasia. On average, less than 5% of uninfected ticks acquired the pathogen while feeding upon infected goats. Although domestic goats are susceptible to the newly described North American isolate of R. slovaca, they are likely to play a minor role in the natural transmission cycle of this pathogen. Our results suggest that goats do not propagate the North American isolate of R. slovaca in peridomestic environments and clinical diagnosis of infection could be difficult due to the brevity and mildness of clinical signs. Further research is needed to elucidate the natural transmission cycle of R. slovaca both in Europe and North America, as well as to identify a more suitable laboratory model.

International Consensus on Allergen Immunotherapy II: Mechanisms, standardization, and pharmacoeconomics.

This article continues the comprehensive international consensus (ICON) statement on allergen immunotherapy (AIT). The initial article also recently appeared in the Journal. The conclusions below focus on key mechanisms of AIT-triggered tolerance, requirements in allergen standardization, AIT cost-effectiveness, and regulatory guidance. Potential barriers to and facilitators of the use of AIT are described in addition to future directions. International allergy specialists representing the European Academy of Allergy and Clinical Immunology; the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma and Immunology; and the World Allergy Organization critically reviewed the existing literature and prepared this summary of recommendations for best AIT practice. The authors contributed equally and reached consensus on the statements presented herein.

Challenges in treating pediatric asthma in developing countries.

Asthma is the most common chronic disease in children in many low- and middle-income countries. In these settings, the burden of childhood asthma is increasing and is associated with severe disease. There are a number of challenges to providing optimal management of childhood asthma in such settings. These include under-diagnosis of childhood asthma, access to care, ability of healthcare workers to manage asthma, availability and affordability of inhaled therapy, environmental control of potential triggers, education of healthcare providers and of the public, and cultural or language issues. International and national guidelines for childhood asthma have been produced, but implementation remains a real challenge. Access to and affordability of essential inhaled asthma drugs, especially low-dose inhaled corticosteroids and short-acting bronchodilators, are major challenges to effective asthma control in many countries. A low-cost spacer made from a plastic bottle is effective for use with a metered-dose inhaler, but use must be included in asthma educational initiatives. Educational programs for healthcare personnel and for the public that are culturally and language appropriate are needed for effective implementation of asthma guidelines. Socioeconomic and structural barriers to care within health services remain obstacles to achieving optimal treatment of asthma for many children.